Effects of Sexual Dimorphism and the Estrous Cycle on <i>Clostridioides difficile</i> Infection Prophylaxis in Two Rodent Models

<i>Clostridioides difficile</i> infection (CDI) is responsible for the majority of identifiable antibiotic-associated diarrhea. Epidemiological studies have consistently shown that women are more at risk for CDI than men. <i>C. difficile</i> is spread by spores that germinate in the antibiotic-altered gut of patients to generate toxin-producing vegetative cells. Since germination is required for CDI, we have shown that cholan-24-amides containing <i>m</i>-sulfanilic acid (CamSA) or aniline (CaPA) inhibit <i>C. difficile</i> spore germination and prevent CDI in rodents. In this study, we found that CDI prophylaxis showed clear sexual dimorphism. Male mice developed less severe CDI but were also more refractory to treatment. On the other hand, anti-germinants protected female mice from developing CDI during most stages of their estrous cycle. Interestingly, infection sexual dimorphism was reversed in hamsters, with male hamsters developing more severe CDI signs than females. Furthermore, anti-germinant compounds protected female hamsters more strongly than male hamsters.